General Information

Chantix (varenicline) is a partial nicotinic acetylcholine
receptor agonist, designed to partially activate this system while
displacing nicotine at its sites of action in the brain.

Chantix is specifically indicated for use as an aid in smoking
cessation.

Chantix is supplied as a capsule for oral administration. The
recommended initial regimen utilizes a 1-week dosing titration: 0.5
mg once daily on days 1-3, and 0.5 mg twice daily on days 4-7,
followed by 1 mg twice daily for 12 weeks, with responders
receiving an additional 12-week treatment course to promote
long-term abstinence.

Clinical Results

FDA Approval
Approval of Chantix was based on six clinical trials, which
enrolled a combined 3659 chronic smokers (at least 10 cigarettes
per day).

Study 1
This dose-ranging placebo-controlled phase II study was designed to
investigate the optimum treatment regimen for the drug. Data from
the study indicated that total doses of 1 mg or 2 mg daily both
promoted successful smoking cessation.

Study 2
This placebo controlled study enrolled 627 patients, who received
0.5 mg or 1 mg Chantix or placebo twice daily for 12 weeks (both
with and without initial 1-week dose titration), with subsequent 40
week observational follow-up. Trial data indicated that 45% of
subjects in the low-dose group and 51% in the high dose group had
CO-confirmed continuous abstinence from weeks 9 to 12, vs. 12% for
placebo. Further, 31% of subjects in each group achieved continuous
abstinence from 1 week after the initiation of dosing through the
end of treatment, vs. 8% for placebo.

Study 3
This placebo-controlled flexible dosing study enrolled 312
subjects, to investigate the effects of a patient-directed dosing
strategy. Subjects received an initial regimen of 0.5 mg twice
daily, followed by a patient-adjusted schedule of 0.5 mg once or
twice daily (freely adjusted). 69% of subjects titrated to the
higher dose at some point during the study; the higher dose was
modal for 44% of subjects. 40% of subjects had CO-confirmed
continuous abstinence for weeks 9-12, vs. 15% for placebo, and 29%
maintained continuous abstinence from the 2 weeks after treatment
initiation through the end of treatment, vs. 9% for placebo.

Studies 4 & 5
These identical, active- and placebo-controlled studies enrolled
1022 (Study 4) and 1023 (Study 5) subjects, who received 1 mg
Chantix twice daily, 150 mg of the approved smoking cessation aid
bupropion sustained-release twice daily, or placebo, for 12 weeks,
with subsequent 40 week observational follow-up. In Study 4,
subjects receiving Chantix achieved superior CO-confirmed smoking
abstinence for weeks 9 through 12 (44%), vs. either bupropion (30%)
or placebo (17%). Smoking-abstinence rate for bupropion was
superior to placebo. 29% of subjects receiving Chantix were
continuously smoking-abstinent from week 2 through the end of
treatment, vs. 23% for bupropion and 12% for placebo. In Study 5,
superior abstinence for weeks 9-12 was achieved with Chantix (44%),
vs. 30% for bupropion and 18% for placebo (bupropion was again
superior to placebo). 29% of Chantix subjects maintained abstinence
for week 2 through the end of treatment, vs. 21% for bupropion and
11% for placebo.

Study 6
This open label study enrolled 1927 chronic smokers, and was
designed to investigate the efficacy of the drug on promoting
long-term smoking abstinence. Subjects received 1 mg Chantix twice
daily for 12 weeks in a run-in period; subjects achiving abstinence
at the end of this regimen were randomized to a double-blind
regimens of either continued Chantix therapy (1 mg twice daily) or
placebo for an additional 12 weeks, with subsequent 28 week
follow-up. Trial data indicated that continuous abstinence for
weeks 13 through 24 was higher for subjects receiving continued
Chantix therapy (70%) than for placebo (50%); this superiority was
maintained through 28 weeks post treatment (54% vs. 39%).

Ongoing Study Commitments

Pfizer comits to conduct a study to determine the multiple-dose
pharmacokinetics of varenicline in pediatric patients in order to
determine the appropriate doses for efficacy and safety evaluations
in adolescent smokers, ages 12 through 16, inclusive, to determine
the adverse event profile in adolescent patients, and to establish
whether there is any age group (or weight group) for whom
varenicline is so poorly tolerated that its utility as an aid to
smoking cessation treatment should not be evaluated in that
group.Final Report Submission: by November 10, 2007

Pfizer commits to conduct a study to determine whether
varenicline, as part of an overall smoking cessation program, is
effective in achieving and maintaining smoking cessation in
tobacco-addicted adolescents, ages 12 through 16, inclusive, to
determine a safe and effective dose, and to document the ability of
treating physicians to select appropriate patients. You will need
to develop a means for determining reliable criteria for
appropriate patient selection of tobacco-addicted teens so that
teenage smokers who are not addicted will not be recruited, and so
that labeling can convey these criteria to physicians who may wish
to use the drug in adolescents.Final Report Submission: by May 10, 2011

Pfizer commits to conduct a prospective epidemiologic cohort
study in pregnant women who are smokers and who are exposed to
varenicline at the time of conception or any time during pregnancy.
This information will be used to assess the potential risk to the
fetus and/or live born infant.Protocol Submission: by November 10, 2006
Study Start: by May 10, 2007
Final Report Submission: by May 10, 2011

Side Effects

Adverse events associated with the use of Chantix may include,
but are not limited to, the following:

Nausea

Insomnia

Headache

Abnormal Dreams

Abdominal Pain

Fatigue/Malaise/Asthenia

Upper Respiratory Tract Disorder

Flatulence

Dry Mouth

Mechanism of Action

Chantix is an alpha-4 beta-2 neuronal nicotinic acetylcholine
receptor agonist. The drug shows high selectiviyty for this
receptor subclass, relative to other nicotinic receptors
(>500-fold alpha-3 beta-4, >3500-fold alpha-7,
>20,000-fold alpha-1 beta gamma delta) or non-nicotinic
receptors and transporters (>2000-fold). The drug competitively
inhibits the ability of nicotine to bind to and activate the
alpha-4 beta-2 receptor. The drug exerts mild agonistic activity at
this site, though at a level much lower than nicotine; it is
presumed that this activation eases withdrawal symptoms.